Compositions Comprising Nebivolol

ABSTRACT

Nebivolol has been shown to be beneficial in the treatment of cardiovascular diseases such hypertension, congestive heart failure, arterial stiffness and endothelial dysfunction. The present invention features a pharmaceutical composition comprising nebivolol and at least one other active agent, wherein the at least one other active agent is a cardiovascular agent.

This application is a divisional of U.S. Non-Provisional patentapplication Ser. No. 11/141,235, filed May 31, 2005, which is based onand claims priority from U.S. Provisional Patent Application Ser. No.60/577,423, Eric Davis, John O'Donnell, Peter Bottini, filed Jun. 4,2004; the disclosures of both are hereby incorporated by reference intheir entirety.

TECHNICAL FIELD

This invention relates to compositions comprising nebivolol and one ormore other active agent. More particularly, this invention relates tocompositions comprising nebivolol and one or more cardiovascular agentsfor the treatment and/or prevention of cardiovascular diseases.

BACKGROUND OF THE INVENTION

Hypertension is a major health concern in the US. Approximately 50million Americans have elevated blood pressure defined as a systolicblood pressure (SBP)≧140 mmHg or a diastolic blood pressure (DBP)≧90mmHg. In addition, individuals with blood pressure of 120/80 mmHg orhigher are at increased risk of developing hypertension and areconsidered to be in a “pre-hypertension” state. Severity of hypertensionis currently classified by stage, with Stage 1 hypertension spanningblood pressure ranges from 140/90 to 159/99 mmHg and Stage 2 includingblood pressures ≧160/100 mmHg.

Onset of hypertension (diastolic alone or in combination with systolic)typically occurs between 25 and 55 years of age. The risk of developinghypertension increases more dramatically with increasing age. Accordingto the CDC, 68.3% of men aged 65-74 have hypertension in the U.S.(Health United States, 2003, CDC/National Center for Health Statistics)and 70.7% of men aged over 75 have hypertension in the U.S. (HealthUnited States, 2003, CDC/National Center for Health Statistics). Inaddition, 73.4% of women aged 65-74 have hypertension in the US (HealthUnited States, 2003, CDC/National Center for Health Statistics) and84.9% of women aged over 75 have hypertension in the US (Health UnitedStates, 2003, CDC/National Center for Health Statistics).

Pharmaceutical formulations that stimulate, agonize, or potentiateendothelial nitric oxide production, particularly formulations thatproduce increased nitric oxide levels in African Americans, are needed.

SUMMARY OF THE INVENTION

In one aspect, the present invention features a pharmaceuticalcomposition comprising nebivolol and at least one other active agent. Ina further embodiment, at least one of the active agents is acardiovascular agent. In a further embodiment, the at least onecardiovascular agent is selected from the group consisting of ACEinhibitors (angiotensin II converting enzyme inhibitors), ARB's(angiotensin II receptor antagonists), adrenergic blockers, adrenergicagonists, agents for pheochromocytoma, antiarrhythmics, antiplateletagents, anticoagulants, antihypertensives, antilipemic agents,antidiabetics, antiinflammatory agents, calcium channel blockers, CETPinhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics,endothelin receptor antagonists, HMG Co-A reductase inhibitors,inotropic agents, rennin inhibitors, vasodialators, vasopressors, AGEcrosslink breakers (advanced glycosylation end-product crosslinkbreakers, such as alagebrium, see U.S. Pat. No. 6,458,819), and AGEformation inhibitors (advanced glycosylation end-product formationinhibitors, such as pimagedine), and mixtures thereof. In oneembodiment, the other cardiovascular agent is an ACE inhibitor or anARB. In a further embodiment, the other cardiovascular agent includes anACE inhibitor and an ARB. In a further embodiment, the ACE inhibitor isselected from the group consisting of: alacepril, benazepril, captopril,ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril,imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat,spirapril, temocapril, trandolapril. In a further embodiment, the ACEinhibitor is enalapril, ramipril, or ramiprilat. In a furtherembodiment, the other cardiovascular agent is an ARB selected from thegroup consisting of candesartan, eprosartan, irbesartan, losartan,valsartan.

In a further embodiment, the pharmaceutical composition comprises anamount of nebivolol in the range of between about 0.125 mg and about 40mg. In a further embodiment, the amount of an ACE inhibitor may be inthe range of between about 0.5 mg to about 80 mg, and/or the amount ofARB may be in the range of between about 1 mg and about 1200 mg.

In a further embodiment, the pharmaceutical composition comprisesnebivolol and only one other active agent. In a further embodiment, thepharmaceutical composition comprises nebivolol and only onecardiovascular agent. In a further embodiment, the cardiovascular agentis selected from the group consisting of ACE inhibitors (angiotensin IIconverting enzyme inhibitors), ARB's (angiotensin II receptorantagonists), adrenergic blockers, adrenergic agonists, agents forpheochromocytoma, anti-anginal agents, antiarrhythmics, antiplateletagents, anticoagulants, antihypertensives, antilipemic agents,antidiabetics, antiinflammatory agents, calcium channel blockers, CETPinhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics,endothelin receptor antagonists, HMG Co-A reductase inhibitors,inotropic agents, rennin inhibitors, vasodialators, vasopressors, AGEcrosslink breakers (advanced glycosylation end-product crosslinkbreakers, such as alagebrium, see U.S. Pat. No. 6,458,819), and AGEformation inhibitors (advanced glycosylation end-product formationinhibitors, such as pimagedine). In a further embodiment, the activeagent is an ACE inhibitor or and ARB.

In another aspect, the present invention features a method of treating asubject for a cardiovascular disorder comprising administering to thesubject an effective amount of nebivolol in combination with at leastone other cardiovascular agent. In a further embodiment, thecardiovascular disorder is selected from the group consisting ofatherosclerosis, hypertension, diabetes mellitus, hyperhomocysteinemia,heart failure, and renal failure.

In another aspect, the present invention features a method of preventinga cardiovascular disorder comprising administration to a subject aneffective amount of nebivolol in combination with an effective amount ofat least one other cardiovascular agent. In a further embodiment, thecardiovascular disorder is selected from the group consisting ofcongestive heart failure, hypertension, pulmonary hypertension,myocardial and cerebral infarctions, atherosclerosis, atherogenesis,thrombosis, ischemic heart disease, post-angioplasty restenosis,coronary artery diseases, renal failure, stable, unstable and variant(Prinzmetal) angina, cardiac edema, renal insufficiency, nephroticedema, hepatic edema, stroke, transient ischemic attacks,cerebrovascular accidents, restenosis, controlling blood pressure inhypertension, platelet adhesion, platelet aggregation, smooth musclecell proliferation, pulmonary edema, and vascular complicationsassociated with the use of medical devices.

In another aspect, the present invention features a kit comprising aneffective amount of nebivolol in combination with an effective amount ofanother cardiovascular agent.

Even though nebivolol has β-blocking properties, nebivolol is differentfrom other classic β-blockers in that it is highly selective to the β1adrenergic receptors and also has vasodilating effects related to itseffect on endothelial nitric oxide. It is believed that nebivololincreases the levels of nitric oxide within the vascular endotheliumthrough the L-arginine-nitric oxide pathway and has been shown toimprove endothelial dysfunction and improve compliance of blood vessels.Nebivolol has also been shown to have antioxidant characteristics whichare favorable to the normal functioning of the vascular endothelium.These characteristics make nebivolol an effective antihypertensive agentwith favorable effects on the vascular endothelium and cardiovascularsystem. Nebivolol has been shown to be beneficial in the treatment ofcardiovascular diseases such as hypertension, congestive heart failure,arterial stiffness and endothelial dysfunction. In part, the presentinvention features a composition comprising nebivolol and anothercardiovascular agent that is believed to work via a different mechanism.

These embodiments of the present invention, other embodiments, and theirfeatures and characteristics, will be apparent from the description,drawings and claims that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a comparison of NO release from Black and White donorendothelial cells after chronic treatment with ramprilat followed bytreatment with nebivolol (1 μM).

FIG. 2 depicts a comparison of the increase in NO release from Black andWhite donor endothelial cells after chronic treatment with ramiprilatfollowed by treatment with nebivolol (1 μM).

FIG. 3 depicts comparison of NO release from Black and White donorendothelial cells after chronic treatment with enalapril followed bytreatment with nebivolol (1 μM).

FIG. 4 depicts a comparison of the increase in NO release from Black andWhite donor endothelial cells after chronic treatment with enalaprilfollowed by treatment with nebivolol (1 μM).

DETAILED DESCRIPTION OF THE INVENTION Definitions

For convenience, before further description of the present invention,certain terms employed in the specification, examples and appendedclaims are collected here. These definitions should be read in light ofthe remainder of the disclosure and understood as by a person of skillin the art. Unless defined otherwise, all technical and scientific termsused herein have the same meaning as commonly understood by a person ofordinary skill in the art.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The phrase “angiotensin converting enzyme inhibitor” or “ACE inhibitor”as used herein refers to a compound that inhibits any enzyme fromconverting angiotensin to any other form.

The phrase “angiotensin II receptor antagonist” or “ARB” refers to acompound that binds to a receptor site on angiotensin II but does notcause any physiological changes unless another receptor ligand ispresent.

The term “antagonist” is art-recognized and refers to a compound thatbinds to a receptor site, but does not cause a physiological changeunless another receptor ligand is present.

The term “bioavailable” is art-recognized and refers to a form of thesubject invention that allows for it, or a portion of the amountadministered, to be absorbed by, incorporated to, or otherwisephysiologically available to a subject or patient to whom it isadministered.

The phrase “cardiovascular agent” or “cardiovascular drug” refers to atherapeutic compound that is useful for treating or preventing acardiovascular disease. Non-limiting examples of suitable cardiovascularagents include ACE inhibitors (angiotensin II converting enzymeinhibitors), ARB's (angiotensin II receptor antagonists), adrenergicblockers, adrenergic agonists, agents for pheochromocytoma, antianginalagents, antiarrhythmics, antiplatelet agents, anticoagulants,antihypertensives, antilipemic agents, antidiabetics, antiinflammatoryagents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors,direct thrombin inhibitors, diuretics, endothelin receptor antagonists,HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors,vasodialators, vasopressors, AGE crosslink breakers (advancedglycosylation end-product crosslink breakers, such as alagebrium, seeU.S. Pat. No. 6,458,819), and AGE formation inhibitors (advancedglycosylation end-product formation inhibitors, such as pimagedine), andcombinations thereof.

Cardiovascular disease or disorder refers to any cardiovascular diseaseor disorder known in the art, including, but not limited to, wherein thecardiovascular disease is selected from the group consisting ofcongestive heart failure, hypertension, pulmonary hypertension,myocardial and cerebral infarctions, atherosclerosis, atherogenesis,thrombosis, ischemic heart disease, post-angioplasty restenosis,coronary artery diseases, renal failure, stable, unstable and variant(Prinzmetal) angina, cardiac edema, renal insufficiency, nephroticedema, hepatic edema, stroke, transient ischemic attacks,cerebrovascular accidents, restenosis, controlling blood pressure inhypertension, platelet adhesion, platelet aggregation, smooth musclecell proliferation, pulmonary edema, and vascular complicationsassociated with the use of medical devices.

The term “combination” refers to two or more different active agentswhich are administered at roughly about the same time (for example,where the active agents are in a single pharmaceutical preparation) orat different times (for example, one agent is administered to thesubject before the other).

The terms “drug,” “pharmaceutically active agent,” “bioactive agent,”“therapeutic agent,” and “active agent” may be used interchangeably andrefer to a substance, such as a chemical compound or complex, that has ameasurable beneficial physiological effect on the body, such as atherapeutic effect in treatment of a disease or disorder, whenadministered in an effective amount. Further, when these terms are used,or when a particular active agent is specifically identified by name orcategory, it is understood that such recitation is intended to includethe active agent per se, as well as pharmaceutically acceptable,pharmacologically active derivatives thereof, or compounds significantlyrelated thereto, including without limitation, salts, pharmaceuticallyacceptable salts, N-oxides, prodrugs, active metabolites, isomers,fragments, analogs, solvates hydrates, radioisotopes, etc.

The phrase “effective amount” refers to that amount of a substance thatproduces some desired local or systemic effect at a reasonablebenefit/risk ratio applicable to any treatment. The effective amount ofsuch substance will vary depending upon the subject and diseasecondition being treated, the weight and age of the subject, the severityof the disease condition, the manner of administration and the like,which can readily be determined by one of ordinary skill in the art.

“Endothelial dysfunction” refers to the impaired ability of in anyphysiological processes carried out by the endothelium, in particular,production of nitric oxide regardless of cause. It may be evaluated by,such as, for example, invasive techniques, such as, for example,coronary artery reactivity to acetylcholine or methacholine, and thelike, or by noninvasive techniques, such as, for example, blood flowmeasurements, brachial artery flow dilation using cuff occlusion of thearm above or below the elbow, brachial artery ultrasonography, imagingtechniques, measurement of circulating biomarkers, such as, asymmetricdimethylarginine (ADMA), and the like. For the latter measurement theendothelial-dependent flow-mediated dialation will be lower in patientsdiagnosed with an endothelial dysfunction.

The phrase “endothelial nitric oxide synthase” or “eNOS” refers toenzymes that produce nitric oxide

The phrase “nebivolol composition” refers to a composition comprisingnebivolol. Nebivolol is a mixture of d and l isomers ofα,α′-[iminobismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol].The composition may include at least one other cardiovascular agent orat least one pharmaceutically acceptable carrier or both.

A “patient,” “subject” or “host” may be a human or non-human animal.

The term “pharmaceutically acceptable salts” is art-recognized andrefers to the relatively non-toxic, inorganic and organic acid additionsalts of compounds, including, for example, those contained incompositions of the present invention.

The term “pharmaceutically acceptable carrier” is art-recognized andrefers to a pharmaceutically-acceptable material, composition orvehicle, such as a liquid or solid filler, diluent, excipient, solventor encapsulating material, involved in carrying or transporting anysubject composition or component thereof from one organ, or portion ofthe body, to another organ, or portion of the body. Each carrier must beacceptable in the sense of being compatible with the subject compositionand its components and not injurious to the patient. Some examples ofmaterials which may serve as pharmaceutically acceptable excipientsinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) excipients, such as cocoa butter and suppository waxes; (9)oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar; (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) IV fluids, including but not limited to Ringer'ssolution, 5% dextrose in water, and half normalsaline; (19) ethylalcohol; (20) phosphate buffer solutions; and (21) other non-toxiccompatible substances employed in pharmaceutical formulations.

The term “prophylactic” or “therapeutic” treatment is art-recognized andrefers to administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if administeredafter manifestation of the unwanted condition, the treatment istherapeutic (i.e., it is intended to diminish, ameliorate or maintainthe existing unwanted condition or side effects therefrom).

The term “structure-activity relationship” or “(SAR)” is art-recognizedand refers to the way in which altering the molecular structure of adrug or other compound alters its interaction with a receptor, enzyme,nucleic acid or other target and the like.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction.

The term “substituted” is also contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissiblesubstituents include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic substituents oforganic compounds. Illustrative substituents include, for example, thosedescribed herein above. The permissible substituents may be one or moreand the same or different for appropriate organic compounds. Forpurposes of this invention, the heteroatoms such as nitrogen may havehydrogen substituents and/or any permissible substituents of organiccompounds described herein which satisfy the valences of theheteroatoms. This invention is not intended to be limited in any mannerby the permissible substituents of organic compounds.

The term “synthetic” is art-recognized and refers to production by invitro chemical or enzymatic synthesis.

The phrase “therapeutic effect” is art-recognized and refers to a localor systemic effect in animals, particularly mammals, and moreparticularly humans caused by a pharmacologically active substance. Theterm thus means any substance intended for use in the diagnosis, cure,mitigation, treatment or prevention of disease or in the enhancement ofdesirable physical or mental development and/or conditions in an animalor human. The phrase “therapeutically-effective amount” means thatamount of such a substance that produces some desired local or systemiceffect at a reasonable benefit/risk ratio applicable to any treatment.The therapeutically effective amount of such substance will varydepending upon the subject and disease condition being treated, theweight and age of the subject, the severity of the disease condition,the manner of administration and the like, which can readily bedetermined by one of ordinary skill in the art.

The term “treating” is art-recognized and refers to curing as well asameliorating at least one symptom of any condition or disease.

Nebivolol

Nebivolol is a β-receptor blocking drug that is a mixture of d- andl-enantiomers, of which d-nebivolol is a highly selective β₁-receptorantagonist.

In addition to its β-receptor blocking properties, nebivolol has beenshown to cause endothelium-dependent vasodilation in both normotensiveand hypertensive subjects. Cockcroft J R, Chowienczyk P J, Brett S E,Chen C P, Dupont A G, Nueten L V, Wooding S J, Ritter J M., Journal ofPharmacology and Experimental Therapeutics. 1995; 274:1067-1071; TzemosN, Lim P O, MacDonald T M., Circulation, 2001; 104:511-514; Broeders MA, Doevendans P A, Bekkers B C, Bronsaer R, van Gorsel E, Heemskerk J W,Egbrink M G, van Breda E, Reneman R S, van Der Zee R., Circulation.2000; 102:677-684. In experimental models, nebivolol has beendemonstrated to stimulate NO release through β₂-adrenergicreceptor-mediated NO production and/or ATP efflux with consequentstimulation of P2Y-purinoceptor-mediated NO release. Broeders M A,Doevendans P A, Bekkers B C, Bronsaer R, van Gorsel E, Heemskerk J W,Egbrink M G, van Breda E, Reneman R S, van Der Zee R., Circulation,2000; 102:677-684; Kalinowski L, Dobrucki L W, Szczepanska-Konkel M,Jankowski M, Martyniec L, Angielski S, Malinski T., Circulation, 2003;107:2747-2752. It has also been reported that nebivolol inhibits NOsynthase uncoupling and produces systemic antioxidant effects. MollnauH, Schulz E, Daiber A, Baldus S, Oelze M, August M, Wendt M, Walter U,Geiger C, Agrawal R, Kleschyov A L, Meinertz T, Thomas Münzel T.,Arteriosclerosis, Thrombosis, and Vascular Biology. 2003; 23:615-621;Troost R, Schwedhelm E, Rojczyk S, Tsikas D, Frolich J C., BritishJournal of Clinical Pharmacology, 2000; 50:377-379.

Compositions Comprising Nebivolol

In part, the present invention features compositions comprisingnebivolol and at least one other active agent, wherein the at least oneother active agent is a cardiovascular agent. The amount of eachcardiovascular agent present in the compositions may vary depending on anumber of variables such as age, weight, gender, and health relatedissues. In general, the dosage of the cardiovascular agents willgenerally be in the range of about 0.01 ng to about 10 g per kg bodyweight, specifically in the range of about 1 ng to about 0.1 g per kg,and more specifically in the range of about 100 ng to about 10 mg perkg. In another embodiment, the amount of nebivolol in the compositionsof the present invention may be anywhere from about 0.125 mg to about 40mg. In one example, when the other cardiovascular agent is an ACEinhibitor, the amount of the ACE inhibitor may be anywhere from 0.5 mgto about 80 mg. When the other cardiovascular agent is an ARB, theamount of ARB may be anywhere from about 1 mg to about 1200 mg. Theamount of the other cardiovascular agent will depend in part on theparticular cardiovascular agent used.

In addition to ACE inhibitors and ARBs, additional cardiovascular agentsinclude, but are not limited to adrenergic blockers, adrenergicagonists, agents for pheochromocytoma, antianginal agents,antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives,antilipemic agents, antidiabetics, antiinflammatory agents, calciumchannel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombininhibitors, diuretics, endothelin receptor antagonists, HMG Co-Areductase inhibitors, inotropic agents, rennin inhibitors,vasodialators, vasopressors, AGE crosslink breakers (advancedglycosylation end-product crosslink breakers, such as alagebrium, seeU.S. Pat. No. 6,458,819), and AGE formation inhibitors (advancedglycosylation end-product formation inhibitors, such as pimagedine).Cardiovascular agents falling within these general categories areexemplified by the following:

“Angiotensin I Converting Enzymes (ACE's) and Angiotensin II ReceptorAntagonists (ARB's)”

“Angiotensin II receptor antagonists” (ARB's) are compounds whichinterfere with the activity of angiotensin II by binding to angiotensinII receptors and interfering with its activity. Angiotensin I andangiotensin II are synthesized by the enzymatic renin-angiotensinpathway. The synthetic process is initiated when the enzyme renin actson angiotensinogen, a pseudoglobulin in blood plasma, to produce thedecapeptide angiotensin I. Angiotensin I is converted by angiotensinconverting enzyme (ACE) to angiotensin II (angiotensin-[1-8]octapeptide). The latter is an active pressor substance which has beenimplicated as a causative agent in several forms of hypertension invarious mammalian species, e.g., humans.

Angiotensin II receptor antagonists (ARB's) are well known and includepeptide compounds and non-peptide compounds. Most angiotensin IIreceptor antagonists are slightly modified congeners in which agonistactivity is attenuated by replacement of phenylalanine in position 8with some other amino acid; stability can be enhanced by otherreplacements that slow degeneration in vivo.

Examples of angiotensin II receptor antagonists include: peptidiccompounds (e.g., saralasin and related analogs); N-substitutedimidazole-2-one (U.S. Pat. No. 5,087,634); imidazole acetate derivativesincluding 2-N-butyl-4-chloro-1-(2-chlorobenzile) imidazole-5-acetic acid(see Long et al., J. Pharmacol. Exp. Ther. 247(1), 1-7 (1988));4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid andanalog derivatives (U.S. Pat. No. 4,816,463); N2-tetrazolebeta-glucuronide analogs (U.S. Pat. No. 5,085,992); substitutedpyrroles, pyrazoles, and tryazoles (U.S. Pat. No. 5,081,127); phenol andheterocyclic derivatives such as 1,3-imidazoles (U.S. Pat. No.5,073,566); imidazo-fused 7-member ring heterocycles (U.S. Pat. No.5,064,825); peptides (e.g., U.S. Pat. No. 4,772,684); antibodies toangiotensin II (e.g., U.S. Pat. No. 4,302,386); and aralkyl imidazolecompounds such as biphenyl-methyl substituted imidazoles (e.g., EP253,310, Jan. 20, 1988); ES8891(N-morpholinoacetyl-(-1-naphthyl)-L-alanyl-(4,thiazolyl)-L-alanyl(35,45)-4-amino-3-hydroxy-5-cyclo-hexapentanoyl-N-hexylamide,Sankyo Company, Ltd., Tokyo, Japan); SKF108566(E-alpha-2-[2-butyl-1-(carboxyphenyl)methyl]1H-imidazole-5-yl[methylane]-2-thiophenepropanoic acid,Smith Kline Beecham Pharmaceuticals, Pa.); Losartan (DUP753/MK954,DuPont Merck Pharmaceutical Company); Remikirin (RO42-5892, F. HoffmanLaRoche A G); A.sub.2 agonists (Marion Merrill Dow) and certainnon-peptide heterocycles (G. D. Searle and Company). Other non-limitingexamples of ARBs include candesartan, eprosartan, irbesartan, losartan,and valsartan. Other ARBs may be identified using standard assayingtechniques known to one of ordinary skill in the art.

“Angiotensin converting enzyme” (ACE) is an enzyme which catalyzes theconversion of angiotensin I to angiotensin II. ACE inhibitors includeamino acids and derivatives thereof, peptides, including di- andtri-peptides and antibodies to ACE which intervene in therenin-angiotensin system by inhibiting the activity of ACE therebyreducing or eliminating the formation of pressor substance angiotensinII. ACE inhibitors have been used medically to treat hypertension,congestive heart failure, myocardial infarction and renal disease.Classes of compounds known to be useful as ACE inhibitors includeacylmercapto and mercaptoalkanoyl prolines such as captopril (U.S. Pat.No. 4,105,776) and zofenopril (U.S. Pat. No. 4,316,906), carboxyalkyldipeptides such as enalapril (U.S. Pat. No. 4,374,829), lisinopril (U.S.Pat. No. 4,374,829), quinapril (U.S. Pat. No. 4,344,949), ramipril (U.S.Pat. No. 4,587,258), and perindopril (U.S. Pat. No. 4,508,729),carboxyalkyl dipeptide mimics such as cilazapril (U.S. Pat. No.4,512,924) and benazapril (U.S. Pat. No. 4,410,520), phosphinylalkanoylprolines such as fosinopril (U.S. Pat. No. 4,337,201) and trandolopril.Other non-limiting examples of ACE inhibitors include, but are notlimited to, alacepril, benazepril, captopril, ceronapril, cilazapril,delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril,perindopril, quinapril, ramipril, ramiprilat, spirapril, temocapril,trandolapril.

Adrenergic Blockers

Non-limiting examples of adrenergic blockers, both α- and β-adrenergicblockers, that may be used in the compositions of the present inventioninclude Beta-adrenergic receptor blockers include, but are not limitedto, atenolol, acebutolol, alprenolol, befunolol, betaxolol, bunitrolol,carteolol, celiprolol, hydroxalol, indenolol, labetalol, levobunolol,mepindolol, methypranol, metindol, metoprolol, metrizoranolol,oxprenolol, pindolol, propranolol, practolol, sotalolnadolol,tiprenolol, tomalolol, timolol, bupranolol, penbutolol, trimepranol,yohimbine,2-(3-(1,1-dimethylethyl)-amino-2-hydroxypropoxy)-3-pyridenecarbonitrilHCl,1-butylamino-3-(2,5-dichlorophenoxy)-2-propanol,1-isopropylamino-3-(4-(2-cyclopropylmethoxyethyl)phenoxy)-2-propanol,3-isopropylamino-1-(7-methylindan-4-yloxy)-2-butanol,2-(3-t-butylamino-2-hydroxy-propylthio)-4-(5-carbamoyl-2-thienyl)thiazol,7-(2-hydroxy-3-t-butylaminpropoxy)phthalide. The above-identifiedcompounds can be used as isomeric mixtures, or in their respectivelevorotating or dextrorotating form.

Adrenergic Agonists

Non-limiting examples of adrenergic agonists, both α- and β-adrenergicagonists, that may be used in the compositions of the present inventioninclude adrafinil, adrenalone, albuterol, amidephrine, apraclonidine,bitolterol, budralazine, carbuterol, clenbuterol, clonidine,clorprenaline, clonidine, cyclopentamine, denopamine, detomidine,dimetofrine, dioxethedrine, dipivefrin, dopexamine, ephedrine,epinephrine, etafedrine, ethylnorepinephrine, fenoterol, fenoxazoline,formoterol, guanabenz, guanfacine, hexoprenaline, hydroxyamphetamine,ibopamine, indanazoline, isoetharine, isometheptene, isoproterenol,mabuterol, mephentermine, metaproterenol, metaraminol, metazoline,methoxamine, methylhexaneamine, methoxyphenamine, midodrine, modafinil,moxonidine, naphazoline, norepinephrine norfenefrine, octodrine,octopamine, oxyfedrine, oxymetazoline, phenylephrine hydrochloride,phenylpropanolamine hydrochloride, phenylpropylmethylamine, pholedrine,pirbuterol prenalterol, procaterol, propylhexedrine, protokylol,pseudoephedrine, reproterol, rilmenidine, rimiterol, ritodrine,salmeterol, solterenol, synephrine, talipexole, terbutaline,tetrahydrozoline, tiamenidine, tramazoline, tretoquinol, tuaminoheptane,tulobuterol, tymazoline, tyramine, xamoterol, xylometazoline, andmixtures thereof.

Agents for Pheochromocytoma

Include but are not limited to chemotherapeutics.

Antiangina Agents

Include but are not limited to amlodipine besylate, amlodipine maleate,betaxolol hydrochloride, bevantolol hydrochloride, butoprozinehydrochloride, carvedilol, cinepazet maleate, metoprolol succinate,molsidomine, monatepil maleate, nitrates (including but not limited toglyceryl trinitrate (GTN, nitroglycerin, Nitro-Bid),isosorbide-5-mononitrate (5-ISMN, Ismo), amyl nitrate and nicorandil(Icorel)), primidolol, ranolazine hydrochloride, tosifen, verapamilhydrochloride).

Antiarrhythmics

Non-limiting examples of antiarrhythmics that may be used in thecompositions of the present invention include acebutolol, acecainide,adenosine, ajmaline, alprenolol, amiodarone, amoproxan, aprindine,aprotinolol, atenolol, azimilide, bevantolol, bidisomide, bretyliumtosylate, bucumolol, butetolol, bunaftine, bunitrolol, bupranolol,butidrine hydrochloride, butobendine, capobenic acid, carazolol,carteolol, cifenline, cloranolol, disopyramide, dofetilide, encainide,esmolol, flecainide, hydroquinidine, ibutilide, indecainide, indenolol,ipratropium bromide, lidocaine, lorajmine, lorcainide, meobentine,mexiletine, moricizine, nadoxolol, nifenaolol, oxprenolol, penbutolol,pentisomide, pilsicainide, pindolol, pirmenol, practolol, prajmaline,procainamide hydrochloride, pronethalol, propafenone, propranolol,pyrinoline, quinidine, sematilide, sotalol, talinolol, tilisolol,timolol, tocainide, verapamil, viquidil, xibenolol, and mixturesthereof.

Antiplatelet Agents

Non-limiting examples of antiplatelet agents that may be used in thecompositions of the present invention include clopidogrel, dipyridamole,abcixamab, and ticlodipine.

Anticoagulants

Anti-coagulant agents are agents which inhibit the coagulation pathwayby impacting negatively upon the production, deposition, cleavage and/oractivation of factors essential in the formation of a blood clot.Non-limiting examples of anticoagulants (i.e, coagulation-relatedtherapy) that may be used in the compositions of the present inventioninclude Aggrenox, Agrylin, Amicar, Anturane, Arixtra, Coumadin, Fragmin,Heparin Sodium, Lovenox, Mephyton, Miradon, Persantine, Plavix, Pletal,Ticlid, Trental, Warfarin. Other “anti-coagulant” and/or “fibrinolytic”agents include Plasminogen (to plasmin via interactions ofprekallikrein, kininogens, Factors XII, XIIIa, plasminogen proactivator,and tissue plasminogen activator[TPA]) Streptokinase; Urokinase:Anisoylated Plasminogen-Streptokinase Activator Complex; Pro-Urokinase;(Pro-UK); rTPA (alteplase or activase; r denotes recombinant); rPro-UK;Abbokinase; Eminase; Sreptase Anagrelide Hydrochloride; Bivalirudin;Dalteparin Sodium; Danaparoid Sodium; Dazoxiben Hydrochloride; EfegatranSulfate; Enoxaparin Sodium; Ifetroban; Ifetroban Sodium; TinzaparinSodium; retaplase; Trifenagrel; Warfarin; Dextrans.

Still other anti-coagulant agents include, but are not limited to,Ancrod; Anticoagulant Citrate Dextrose Solution; Anticoagulant CitratePhosphate Dextrose Adenine Solution; Anticoagulant Citrate PhosphateDextrose Solution; Anticoagulant Heparin Solution; Anticoagulant SodiumCitrate Solution; Ardeparin Sodium; Bivalirudin; Bromindione; DalteparinSodium; Desirudin; Dicumarol; Heparin Calcium; Heparin Sodium; LyapolateSodium; Nafamostat Mesylate; Phenprocoumon; Tinzaparin Sodium.

Inhibitors of platelet function are agents that impair the ability ofmature platelets to perform their normal physiological roles (i.e.,their normal function). Platelets are normally involved in a number ofphysiological processes such as adhesion, for example, to cellular andnon-cellular entities, aggregation, for example, for the purpose offorming a blood clot, and release of factors such as growth factors(e.g., platelet-derived growth factor (PDGF)) and platelet granularcomponents. One subcategory of platelet function inhibitors areinhibitors of platelet aggregation which are compounds which reduce orhalt the ability of platelets to associate physically with themselves orwith other cellular and non-cellular components, thereby precluding theability of a platelet to form a thrombus.

Examples of useful inhibitors of platelet function include but are notlimited to acadesine, anagrelide (if given at doses exceeding 10mg/day), anipamil, argatroban, aspirin, clopidogrel, cyclooxygenaseinhibitors such as nonsteroidal anti-inflammatory drugs and thesynthetic compound FR-122047, danaparoid sodium, dazoxibenhydrochloride, diadenosine 5′,5′″-P1,P4-tetraphosphate (Ap4A) analogs,difibrotide, dilazep dihydrochloride, 1,2- and 1,3-glyceryl dinitrate,dipyridamole, dopamine and 3-methoxytyramine, efegatran sulfate,enoxaparin sodium, glucagon, glycoprotein IIb/IIIa antagonists such asRo-43-8857 and L-700,462, ifetroban, ifetroban sodium, iloprost,isocarbacyclin methyl ester, isosorbide-5-mononitrate, itazigrel,ketanserin and BM-13.177, lamifiban, lifarizine, molsidomine,nifedipine, oxagrelate, PGE, platelet activating factor antagonists suchas lexipafant, prostacyclin (PGI.sub.2), pyrazines, pyridinol carbamate,ReoPro (i.e., abciximab), sulfinpyrazone, synthetic compounds BN-50727,BN-52021, CV-4151, E-5510, FK-409, GU-7, KB-2796, KBT-3022, KC-404,KF-4939, OP-41483, TRK-100, TA-3090, TFC-612 and ZK-36374,2,4,5,7-tetrathiaoctane, 2,4,5,7-tetrathiaoctane 2,2-dioxide,2,4,5-trithiahexane, theophyllin pentoxifyllin, thromboxane andthromboxane synthetase inhibitors such as picotamide and sulotroban,ticlopidine, tirofiban, trapidil and ticlopidine, trifenagrel,trilinolein, 3-substituted 5,6-bis(4-methoxyphenyl)-1,2,4-triazines, andantibodies to glycoprotein IIb/IIIa as well as those disclosed in U.S.Pat. No. 5,440,020, and anti-serotonin drugs, Clopridogrel;Sulfinpyrazone; Aspirin; Dipyridamole; Clofibrate; Pyridinol Carbamate;PGE; Glucagon; Antiserotonin drugs; Caffeine; Theophyllin Pentoxifyllin;Ticlopidine.

Antihypertensives

Non-limiting examples of antihypertensives that may be used in thecompositions of the present invention include amlodipine, benidipine,benezepril, candesartan, captopril, darodipine, dilitazem HCl,diazoxide, doxazosin HCl, enalapril, eposartan, losartan mesylate,felodipine, fenoldopam, fosenopril, guanabenz acetate, irbesartan,isradipine, lisinopril, mecamylamine, minoxidil, nicardipine HCl,nifedipine, nimodipine, nisoldipine, phenoxybenzamine HCl, prazosin HCl,quinapril, reserpine, terazosin HCl, telmisartan, and valsartan.

Antilipemic Agents

Non-limiting examples of antilipemic agents that may be used in thecompositions of the present invention include acipimox, aluminumnicotinate, atorvastatin, cholestyramine resin, colestipol, polidexide,beclobrate bezafibrate, ciprofibrate, clinofibrate, clofibrate,clofibric acid, etofibrate, fenofibrate, fluvastatin, gemfibrozil,lovastatin, lysosomal acid lipase, icofibrate, niacin, pirifibrate,pravastatin sodium, ronifibrate, simfibrate, theofibrate, simvastatin,niceritrol, nicoclonate, nicomol. oxiniacic acid, etiroxate, thyopropicacid, thyroxine, acifran, azacosterol, benfluorex,beta-benzalbutyramide, carnitine, chondroitin sulfate clomestrone,detaxtran, dextran sulfate sodium, 5, 8, 11, 14, 17-eicosapentaenoicacid, eritadenine, furazabol, meglutol, melinamide, mytatrienediol,ornithine, gamma-oryzanol, pantethine, pentaerythritol tetraacetate,alpha-phenylbutyramide, pirozadil, probucol, beta-sitosterol, sultosilicacid (piperazine salt), tiadenol, triparanol, xenbucin, and mixturesthereof.

Antidiabetics

Non-limiting examples of antidiabetics that may be used in thecompositions of the present invention include biguanides such asbuformin, metformin, and phenformin; hormones such as insulin;sulfonylurea derivatives such as acetohexamide, 1-butyl-3-metanilylurea,carbutamide, chlorpropamide, glibornuride, gliclazide, glimepiride,glipizide, gliquidone, glisoxepid, glyburide, glybuthiazole, glybuzole,glyhexamide, glymidine, glypinamide, phenbutamide, tolazamide,tolbutamide, tolcyclamide; HDL agonists; PPARγ agonists such asthiazolidinediones such as pioglitazone, rosiglitazone, andtroglitazone; and others including acarbose, calcium mesoxalate,miglitol, and repaglinide.

Antiinflammatory Agents

Non-limiting examples of antiinflammatory agents that may be used in thecompositions of the present invention include Alclofenac; AlclometasoneDipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide;Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac;Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen;Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide;Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate;Clobetasone Butyrate; Clopirac; Cloticasone Propionate; CormethasoneAcetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone;Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium;Diflorasone Diacetate; Diflumidone Sodium; Diflunisal; Difluprednate;Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab;Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole;Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac;Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate;Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate;Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate;Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; HalopredoneAcetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol;Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole;Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen;Lofemizole Hydrochloride; Lomoxicam; Loteprednol Etabonate;Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate;Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate;Morniflumate; Nabumetone; Naproxen; Naproxen Sodium; Naproxol; Nimazone;Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone;Paranyline Hydrochloride; Pentosan Polysulfate Sodium; PhenbutazoneSodium Glycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; PiroxicamOlamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone;Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex;Salnacedin; Salsalate; Salycilates; Sanguinarium Chloride; Seclazone;Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate;Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam;Tesimide; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; TolmetinSodium; Triclonide; Triflumidate; Zidometacin; Glucocorticoids;Zomepirac Sodium. One preferred antiinflammatory agent is aspirin.

Calcium Channel Blockers

Calcium channel blockers are a chemically diverse class of compoundshaving important therapeutic value in the control of a variety ofdiseases including several cardiovascular disorders, such ashypertension, angina, and cardiac arrhythmias (Fleckenstein, Cir. Res.v. 52, (suppl. 1), p. 13-16 (1983); Fleckenstein, Experimental Facts andTherapeutic Prospects, John Wiley, New York (1983); McCall, D., CurrPract Cardiol, v. 10, p. 1-11 (1985)). Calcium channel blockers are aheterogeneous group of drugs that prevent or slow the entry of calciuminto cells by regulating cellular calcium channels. (Remington, TheScience and Practice of Pharmacy, Nineteenth Edition, Mack PublishingCompany, Eaton, Pa., p. 963 (1995)). Most of the currently availablecalcium channel blockers, and useful according to the present invention,belong to one of three major chemical groups of drugs, thedihydropyridines, such as nifedipine, the phenyl alkyl amines, such asverapamil, and the benzothiazepines, such as diltiazem. Non-limitingexamples of calcium channel blockers that may be used in thecompositions of the present invention include bepridil, clentiazem,diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil,terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine,cilnidipine, efonidipine, elgodipine, felodipine, isradipine,lacidipine, lercanidpine, manidipine, nicardipine, nifedipine,nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine,flunarizine, lidoflazine, lomerizine, bencyclane, etafenone,fantofarone, perhexyline, and mixtures thereof.

CETP Inhibitors

A non-limiting example of a CETP inhibitor that may be used in thecompositions of the present invention includes torcetrapib.

COX-2 Inhibitors

Non-limiting examples of COX-2 inhibitors that may be used in thecompositions of the present invention include compounds according to thefollowing: all of the compounds and substances beginning on page 8 ofWinokur WO99/20110 as members of three distinct structural classes ofselective COX-2 inhibitor compounds, and the compounds and substanceswhich are selective COX-2 inhibitors in Nichtberger, U.S. Pat. No.6,136,804, Oct. 24, 2000, entitled “Combination therapy for treating,preventing, or reducing the risks associated with acute coronaryischemic syndrome and related conditions”, and the compounds andsubstances which are selective COX-2 inhibitors in Isakson et al, PCTapplication WO/09641645 published Dec. 27, 1996, filed as PCT/US 9509905on Jun. 12, 1995, entitled “Combination of a Cyclooxygenase-2 Inhibitorand a Leukotriene B4 Receptor Antagonist for the Treatment ofInflammations.” The meaning of COX-2 inhibitor in this invention shallinclude the compounds and substances referenced and incorporated intoWinokur WO99/20110 by reference to art therein, the compounds andsubstances referenced and incorporated into Nichtberger, U.S. Pat. No.6,136,804, Oct. 24, 2000, by reference to art therein, and the compoundsand substances which are COX-2 inhibitors referenced and incorporatedinto Isakson et al, PCT application WO/09641645 published Dec. 27, 1996,filed as PCT/US 9509905 on Jun. 12, 1995, entitled “Combination of aCyclooxygenase-2 Inhibitor and a Leukotriene B4 Receptor Antagonist forthe Treatment of Inflammations.” The meaning of COX-2 inhibitor in thisinvention also includes rofecoxib, and celecoxib, marketed as VIOXX andCELEBREX by Merck and Searle/Pfizer respectively. Rofecoxib is discussedin Winokur, WO99/20110 as compound 3, on p. 9. Celecoxib is discussed asSC-58635 in the same reference, and in T. Penning, Synthesis andbiological evaluation of the 1,5-diarylpyrazole class ofcyclooxygenase-2 inhibitors: identification of4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrozol-1-yl]benzenesulfonamide(SC-58635, celecoxib)”, J. Med. Chem. Apr. 25, 1997: 40(9): 1347-56. Themeaning of COX-2 inhibitor in this invention also includes SC299referred to as a fluorescent diaryloxazole. C. Lanzo et al,“Fluorescence quenching analysis of the association and dissociation ofa diarylheterocycle to cyclooxygenasel-1 and cyclooxygenase-2: dynamicbasis of cycloxygenase-2 selectivity”, Biochemistry May 23, 2000, vol.39(20):6228-34, and in J. Talley et al, “4,5-Diaryloxazole inhibitors ofcyclooxygenase-2 (COX-2)”, Med. Res. Rev. May 1999; 19(3): 199-208. Themeaning of COX-2 inhibitor in this invention also includes valdecoxib,See, “4-[5-Methyl-3-phenylisoxazol-1-yl]benzenesulfonamide, Valdecoxib:A Potent and Selective Inhibitor of COX-2”, J. Med. Chem. 2000, Vol. 43:775-777, and parecoxib, sodium salt or parecoxib sodium, See,N-[[(5-methyl-3-phenylixoxazol-4yl)-phenyl]sulfonyl]propanimide, SodiumSalt, Parecoxib Sodium: A Potent and Selective Inhibitor of COX-2 forParenteral Administration”, J. Med. Chem. 2000, Vol. 43: 1661-1663. Themeaning of COX-2 inhibitor in this invention also includes thesubstitution of the sulfonamide moiety as a suitable replacement for themethylsulfonyl moiety. See, J. Carter et al, Synthesis and activity ofsulfonamide-substituted 4,5-diaryl thiazoles as selectivecyclooxygenase-2 inhibitors.” Bioorg. Med. Chem. Lett Apr. 19, 1999:Vol. 9(8): 1171-74, and compounds referenced in the article “Design andsynthesis of sulfonyl-substituted 4,5-diarylthiazoles as selectivecyclooxygenase-2 inhibitors”, Bioorg. Med. Chem. Lett Apr. 19, 1999:Vol. 9(8): 1167-70. The meaning of this invention includes a COX-2inhibitor, NS398 referenced in two articles: Attiga et al, “Inhibitorsof Prostaglandin Synthesis Inhibit Human Prostate Tumor CellInvasiveness and Reduce the Release of Matrix Metalloproteinases”, 60Cancer Research 4629-4637, Aug. 15, 2000, and in “The cyclooxygenase-2inhibitor celecoxib induces apoptosis by blocking Akt activation inhuman prostate cancer cells independently of Bcl-2,” Hsu et al, 275(15)J. Biol. Chem. 11397-11403 (2000). The meaning of COX-2 inhibitor inthis invention includes the cyclo-oxygenase-2 selective compoundsreferenced in Mitchell et al, “Cyclo-oxygenase-2: pharmacology,physiology, biochemistry and relevance to NSAID therapy”, Brit. J. ofPharmacology (1999) vol. 128: 1121-1132, see especially p. 1126. Themeaning of COX-2 inhibitor in this invention includes so-calledNO-NSAIDs or nitric oxide-releasing-NSAIDs referred to in L. Jackson etal, “COX-2 Selective Nonsteroidal Anti-Inflammatory Drugs: Do TheyReally Offer Any Advantages?”, Drugs, June, 2000 vol. 59(6): 1207-1216and the articles at footnotes 27, and 28. Also included in the meaningof COX-2 inhibitor in this invention includes any substance thatselectively inhibits the COX-2 isoenzyme over the COX-1 isoenzyme in aratio of greater than 10 to 1 and preferably in ratio of at least 40 to1 as referenced in Winokur WO 99/20110, and has one substituent havingboth atoms with free electrons under traditionalvalence-shell-electron-pair-repulsion theory located on a cyclic ring(as in the sulfylamine portion of celecoxib), and a second substituentlocated on a different ring sufficiently far from said first substituentto have no significant electron interaction with the first substituent.The second substituent should have an electronegativity within suchsubstituent greater than 0.5, or the second substituent should be anatom located on the periphery of the compound selected from the group ofa halogen F, Cl, Br or I, or a group VI element, S or O. Thus forpurposes of this last included meaning of a COX-2 inhibitor, one portionof the COX-2 inhibitor should be hydrophilic and the other portionlipophilic. Also included as a COX-2 inhibitor are compounds listed atpage 553 in Pharmacotherapy: A Pathophysiologic Approach, Depiro et al(McGraw Hill 1999) including nabumetone and etodolac. Recognizing thatthere is overlap among the selective COX-2 inhibitors set out in thisparagraph, the intent of the term COX-2 inhibitor is to comprehensivelyinclude all selective COX-2 inhibitors, selective in the sense ofinhibiting COX-2 over COX-1. The inventors add to the class of COX-2inhibitors useful in the invention the drug bearing the name etoricoxibreferenced in the Wall Street Journal, Dec. 13, 2000, manufactured byMerck. See, also, Chauret et al., “In vitro metabolism considerations,including activity testing of metabolites, in the discovery andselection of the COX-2 inhibitor etoricoxib (MK-0663),” Bioorg. Med.Chem. Lett. 11(8): 1059-62 (Apr. 23, 2001). Another selective COX-2inhibitor is DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone] referenced in Yergey et al, Drug Metab. Dispos.29(5):638-44 (May 2001). The inventors also include as a selective COX-2inhibitor the flavonoid antioxidant silymarin, and an active ingredientin silymarin, silybinin, which demonstrated significant COX-2 inhibitionrelative to COX-1 inhibition. The silymarin also showed protectionagainst depletion of glutathione peroxidase. Zhao et al, “SignificantInhibition by the Flavonoid Antioxidant Silymarin against12-O-tetracecanoylphorbol 13-acetate-caused modulation of antioxidantand inflammatory enzymes, and cyclooxygenase 2 and interleukin-1 alphaexpression in SENCAR mouse epidermis: implications in the prevention ofstage I tumor promotion,” Mol. Carcinog. December 1999, Vol 26(4):321-33PMID 10569809. Silymarin has been used to treat liver diseases inEurope.

A number of the above-identified COX-2 inhibitors are prodrugs ofselective COX-2 inhibitors, and exert their action by conversion in vivoto the active and selective COX-2 inhibitors. The active and selectiveCOX-2 inhibitors formed from the above-identified COX-2 inhibitorprodrugs are described in detail in WO 95/00501, published Jan. 5, 1995,WO 95/18799, published Jul. 13, 1995 and U.S. Pat. No. 5,474,995, issuedDec. 12, 1995. Given the teachings of U.S. Pat. No. 5,543,297, entitled:“Human cyclooxygenase-2 cDNA and assays for evaluating cyclooxygenase-2activity,” a person of ordinary skill in the art would be able todetermine whether an agent is a selective COX-2 inhibitor or a precursorof a COX-2 inhibitor, and therefore part of the present invention.

“Direct Thrombin Inhibitors”

Non limiting examples of direct thrombin inhibitors include hirudin,hirugen, hirulog, agatroban, PPACK, and thrombin aptamers.

Diuretics

Non-limiting examples of diuretics that may be used in the compositionsof the present invention include althiazide, bendroflumethiazide,benzthiazide, buthiazide, chlorthalidone, cyclopenthiazide,cyclothiazide, epithiazide, ethiazide, fenquizone, indapamide,hydroflumethiazide, methyclothiazide, meticrane, metolazone,paraflutizide, polythiazide, quinethazone, teclothiazide,trichloromethiazide, chlormerodrin, meralluride, mercamphamide,mercaptomerin sodium, mercumatilin sodium, mercurous chloride, mersalyl,acefylline, 7-morpholinomethyl-theophylline, pamabrom, protheobromine,theobromine, canrenone, oleandrin, spironolactone, acetazolamide,ambuside, azosemide, bumetanide, butazolamide, clopamide, clrexolone,disufamide, ethoxzolamide, furosemide, mefruside, methazolamide,piretanide, torsemide, tripamide, xipamide, aminometradine,amisometradine, amanozine, amiloride, arbutin, chlorazanil, ethacrynicacid, etozolin, hydracarbazine, isosorbide, mannitol, metochalcone,muzolimine, perhexyline, ticrynafen, triamterene, urea, and mixturesthereof.

Endothelin Receptor Antagonists

A non-limiting example of an endothelin receptor antagonist that may beused in the compositions of the present invention is bosentan.

HMG-CoA Reductase Inhibitor (Statins)

HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase is themicrosomal enzyme that catalyzes the rate limiting reaction incholesterol biosynthesis (HMG-CoA6Mevalonate). An HMG-CoA reductaseinhibitor inhibits HMG-CoA reductase, and as a result inhibits thesynthesis of cholesterol. A number of HMG-CoA reductase inhibitors hasbeen used to treat individuals with hypercholesterolemia. More recently,HMG-CoA reductase inhibitors have been shown to be beneficial in thetreatment of stroke (Endres M, et al., Proc Natl Acad Sci USA, 1998,95:8880-5).

HMG-CoA reductase inhibitors useful for co-administration with theagents of the invention include, but are not limited to, simvastatin(U.S. Pat. No. 4,444,784), lovastatin (U.S. Pat. No. 4,231,938),pravastatin sodium (U.S. Pat. No. 4,346,227), fluvastatin (U.S. Pat. No.4,739,073), atorvastatin (U.S. Pat. No. 5,273,995), cerivastatin, andnumerous others described in U.S. Pat. Nos. 5,622,985; 5,135,935;5,356,896; 4,920,109; 5,286,895; 5,262,435; 5,260,332; 5,317,031;5,283,256; 5,256,689; 5,182,298; 5,369,125; 5,302,604; 5,166,171;5,202,327; 5,276,021; 5,196,440; 5,091,386; 5,091,378; 4,904,646;5,385,932; 5,250,435; 5,132,312; 5,130,306; 5,116,870; 5,112,857;5,102,911; 5,098,931; 5,081,136; 5,025,000; 5,021,453; 5,017,716;5,001,144; 5,001,128; 4,997,837; 4,996,234; 4,994,494; 4,992,429;4,970,231; 4,968,693; 4,963,538; 4,957,940; 4,950,675; 4,946,864;4,946,860; 4,940,800; 4,940,727; 4,939,143; 4,929,620; 4,923,861;4,906,657; 4,906,624 and 4,897,402, the disclosures of which patents areincorporated herein by reference.

Other non-limiting examples of HMG-CoA reductase inhibitors that may beused in the compositions of the present invention include mevastatin,pitavastatin, rosuvastatin, gemcabene, and probucol.

Inotropic Agents

Non-limiting examples of inotropic agents that may be used in thecompositions of the present invention include acefylline,acetyldigitoxins, 2-amino-4-picoline, amrinone, benfurodilhemisuccinate, bucladesine, camphotamide, convallatoxin, cymarin,denopamine, deslanoside, digitalin, digitalis, digitoxin, digoxin,dobutamine, docarpamine, dopamine, dopexamine, enoximone,erythrophleine, fenalsomine, gitalin, gitoxin, glycocyamine, heptaminol,hydrastinine, ibopamine, lanatosides, loprinine, milrinone, nerifolin,oleandrin, ouabain, oxyfedrine, pimobendan, prenalterol, proscillaridin,resibufogenin, scillaren, scillarenin, strophanthin, sulmazole,theobromine, vesnarinone, xamoterol, and mixtures thereof.

“Renin Inhibitors”

Renin inhibitors are compounds which interfere with the activity ofrenin. Renin inhibitors include amino acids and derivatives thereof,peptides and derivatives thereof, and antibodies to renin. Examples ofrenin inhibitors that are the subject of United States patents are asfollows: urea derivatives of peptides (U.S. Pat. No. 5,116,835); aminoacids connected by nonpeptide bonds (U.S. Pat. No. 5,114,937); di- andtri-peptide derivatives (U.S. Pat. No. 5,106,835); amino acids andderivatives thereof (U.S. Pat. Nos. 5,104,869 and 5,095,119); diolsulfonamides and sulfinyls (U.S. Pat. No. 5,098,924); modified peptides(U.S. Pat. No. 5,095,006); peptidyl beta-aminoacyl aminodiol carbamates(U.S. Pat. No. 5,089,471); pyrolimidazolones (U.S. Pat. No. 5,075,451);fluorine and chlorine statine or statone containing peptides (U.S. Pat.No. 5,066,643); peptidyl amino diols (U.S. Pat. Nos. 5,063,208 and4,845,079); N-morpholino derivatives (U.S. Pat. No. 5,055,466);pepstatin derivatives (U.S. Pat. No. 4,980,283); N-heterocyclic alcohols(U.S. Pat. No. 4,885,292); monoclonal antibodies to renin (U.S. Pat. No.4,780,401); and a variety of other peptides and analogs thereof (U.S.Pat. Nos. 5,071,837, 5,064,965, 5,063,207, 5,036,054, 5,036,053,5,034,512, and 4,894,437).

Vasodilators

Non-limiting examples of vasodilators that may be used in thecompositions of the present invention include bencyclane, cinnarizine,citicoline, cyclandelate, ciclonicate, diisopropylamine dichloroacetate,eburnamonine, fasudil, fenoxedil, flunarizine, ibudilast, ifenprodil,isosorbide dinitrate, lomerixine, nafronyl, nicametate, nicergoline,nimodipine, papaverine, pentifylline, tinofedrine, vancamine,vinpocetine, viquidil, amotriphene, bendazol, benfurodil hemisuccinate,benziodarone, chloracizine, chromonar, clobenfurol, clonitrate,cloricromen, dilazep, dipyridamole, droprenilamine, efloxate, erythrityltetranitrate, etafenone, fendiline, floredil, ganglefence, heart muscleextract, hexestrol bis(β-diethylaminoethyl ether), hexobendine,hydralazine, itramin tosylate khellin, lidoflazine, mannitolhexanitrate, medibazine, nitroglycerin, isosorbide mononitrate,isosorbide dinitrate, and other nitrates, pentaerythritol tetranitrate,pentrinitrol, perhexyline, pimefylline, prenylamine, propatyl nitrate,pyridofylline, trapidil, tricromyl, trimetazidine, trolnitratephosphate, visnadine, aluminum nicotinate, bamethan, bencyclane,betahistine, bradykinin, brovincamine, bufeniode, buflomedil,butalamine, cetiedil, ciclonicate, cinepazide, cinnarizine,cyclandelate, diisopropylamine dichloroacetate, eledoisin, fenoxedil,flunazine, hepronicate, ifenprodil, iloprost, inositol niacinate,isoxsuprine, kallidin, kallikrein, moxisylyte, nafronyl, nicametatenicergoline, nicofuranose, nicotinyl alcohol, nylidrin, pentifylline,pentoxifylline, piribedil, prostaglandin E₁, suloctidil, tolazoline,xanthinol niacinate, and mixtures thereof.

Vasopressors

Non-limiting examples of vasopressors that may be used in thecompositions of the present invention include amezinium methyl sulfate,angiotensin amide, dimetofrine, dopamine, etifelmin, etilefrin,gepefrine, metaraminol, methoxamine, midodrine, norepinephrine,pholedrine, synephrine, and mixtures thereof.

Age Crosslink Breakers (Advanced Glycosylation End-Product CrosslinkBreakers)

Non-limiting examples of AGE crosslink breakers that may be used in thecompositions of the present invention include Alagebrium.

Age Formation Inhibitors (Advanced Glycosylation End-Product FormationInhibitors)

Non-limiting examples of AGE formation inhibitors that may be used inthe compositions of the present invention include Pimagedine.

Other Actives:

Non-limiting examples of other active ingredients that may be combinedwith these nebivolol compositions include, but are not limited to, thefollowing representative classes of compounds, as well as theirpharmaceutically acceptable salts, isomers, esters, ethers and otherderivatives:

analgesics and anti-inflammatory agents, such as aloxiprin, auranofin,azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal,etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen,indomethacin, ketoprofen, ketorolac, leflunomide, meclofenaminc acid,mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone,phenylbutazone, piroxicam, rofecoxib, sulindac, tetrahydrocannabinol,tramadol and tromethamine;

antihelminthics, such as albendazole, bephenium hydroxynaphthoate,cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine,oxfendazole, oxantel embonate, praziquantel, pyrantel embonate andthiabendazole;

anti-asthma agents, such as zileuton, zafirlukast, terbutaline sulfate,montelukast, and albuterol;

anti-bacterial agents, such as alatrofloxacin, azithromycin, baclofen,benzathine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin,clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline,

erythromycin, ethionamide, furazolidone, grepafloxacin, imipenem,levofloxacin, lorefloxacin, moxifloxacin HCl, nalidixic acid,nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutine,rifapentine, sparfloxacin,

spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine,

ulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole,sulphapyridine, tetracycline, trimethoprim, trovafloxacin, andvancomycin;

anti-viral agents, such as abacavir, amprenavir, delavirdine, efavirenz,indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir,and stavudine;

anti-depressants, such as amoxapine, bupropion, citalopram,clomipramine, fluoxetine HCl, maprotiline HCl, mianserin HCl,nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl,trimipramine maleate, and venlafaxine HCl;

anti-epileptics, such as beclamide, carbamazepine, clonazepam, ethotoin,felbamate, fosphenytoin sodium, lamotrigine, methoin, methsuximide,methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide,

phenobarbitone, phenyloin, phensuximide, primidone, sulthiame, tiagabineHCl, topiramate, valproic acid, and vigabatrin;

anti-fungal agents, such as amphotericin, butenafine HCl, butoconazolenitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine,griseofulvin, itraconazole, ketoconazole, miconazole, natamycin,

nystatin, sulconazole nitrate, oxiconazole, erbinafine HCl, terconazole,tioconazole and undecenoic acid;

anti-gout agents, such as allopurinol, probenecid and sulphinpyrazone;

anti-malarials, such as amodiaquine, chloroquine, chlorproguanil HCl,halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine andquinine sulfate;

anti-migraine agents, such as dihydroergotamine mesylate, ergotaminetartrate, frovatriptan, methysergide maleate, naratriptan HCl, pizotifenmaleate, rizatriptan benzoate, sumatriptan succinate, and zolmitriptan;

anti-muscarinic agents, such as atropine, benzhexol HCl, biperiden,ethopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencyclimineHCl and tropicamide;

anti-neoplastic agents and immunosuppressants, such asaminoglutethimide, amsacrine, azathioprine, bicalutamide, bisantrene,busulfan, camptothecin, capecitabine, chlorambucil, cyclosporin,dacarbazine,

ellipticine, estramustine, etoposide, irinotecan, lomustine, melphalan,mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, mofetilmycophenolate, nilutamide, paclitaxel, procarbazine HCl, sirolimus,tacrolimus, tamoxifen citrate, teniposide, testolactone, topotecan HCl,and toremifene citrate;

anti-protozoal agents, such as atovaquone, benznidazole, clioquinol,decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide,furazolidone, metronidazole, nimorazole, nitrofurazone, ornidazole andtinidazole;

anti-psychotics, such as aripiprazole, clozapine, ziprasidone,haloperidol, molindone, loxapine, thioridazine, molindone, thiothixene,pimozide, fluphenazine, risperidone mesoridazine, quetiapine,trifluoperazine, chlorprothixene, chlorpromazine, perphenazine,trifluopromazine, olanzapine;

anti-thyroid agents, such as carbimazole, paracalcitol, andpropylthiouracil;

anti-tussives, such as benzonatate;

anxiolytics, sedatives, hypnotics and neuroleptics, such as alprazolam,amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol,brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole,chlorpromazine, chlorprothixene, clonazepam, clobazam, clotiazepam,clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam,triflupromazine, flupenthixol decanoate, fluphenthixol decanoate,flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam,meprobamate, mesoridazine, methaqualone, methylphenidate, midazolam,molindone, nitrazepam,

olanzapine, oxazepam, pentobarbitone, perphenazine pimozide,prochlorperazine, pseudoephedrine, quetiapine, risperidone, sertindole,sulpiride, temazepam, thioridazine, triazolam, zolpidem, and zopiclone;

corticosteroids, such as beclomethasone, betamethasone, budesonide,cortisone acetate, desoxymethasone, dexamethasone, fludrocortisoneacetate, flunisolide, fluocortolone, fluticasone propionate,hydrocortisone, methylprednisolone, prednisolone, prednisone andtriamcinolone;

anti-parkinsonian agents, such as apomorphine, bromocriptine mesylate,lysuride maleate, pramipexole, ropinirole HCl, and tolcapone;

gastro-intestinal agents, such as bisacodyl, cimetidine, cisapride,diphenoxylate HCl, domperidone, famotidine, lanosprazole, loperamide,mesalazine, nizatidine, omeprazole, ondansetron HCL, rabeprazole sodium,ranitidine HCl and sulphasalazine;

keratolytics, such as acetretin, calciprotriene, calcifediol,calcitriol, cholecalciferol, ergocalciferol, etretinate, retinoids,targretin, and tazarotene;

lipid regulating agents, such as atorvastatin, bezafibrate,cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin,gemfibrozil, pravastatin, probucol, and simvastatin;

muscle relaxants, such as dantrolene sodium and tizanidine HCl;

nutritional agents, such as calcitriol, carotenes, dihydrotachysterol,essential fatty acids, non-essential fatty acids, phytonadiol, vitaminA, vitamin B.sub.2, vitamin D, vitamin E and vitamin K;

opioid analgesics, such as codeine, dextropropoxyphene, diamorphine,dihydrocodeine, fentanyl, meptazinol, methadone, morphine, nalbuphineand pentazocine;

sex hormones, such as clomiphene citrate, cortisone acetate, danazol,dehydroepiandrosterone, ethynyl estradiol, finasteride, fludrocortisone,fluoxymesterone, medroxyprogesterone acetate, megestrol acetate,mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol,conjugated estrogens,

progesterone, rimexolone, stanozolol, stilbestrol, testosterone andtibolone;

stimulants, such as amphetamine, dexamphetamine, dexfenfluramine,fenfluramine and mazindol;

drugs for rheumatoid arthritis such as methotrexate, auranofin,aurothioglucose and gold sodium thiomalate;

drugs for osteoporosis such as alendronate and raloxifene;

local anesthetics;

anti-herpes drugs such as acyclovir, valacyclovir and famcyclovir;

anti-emetics such as ondansetron and granisetron;

Further examples of other active agents which may be suitable for thisinvention include, without limitation: abecarnil, acamprostate, acavir,acebutolol, aceclofenac, acemetacin, acetaminophen, acetaminosalol,acetanilide, acetohexamide, acetophenazine maleate, acetophenazine,acetoxolone, acetoxypregnenolone, acetretin, acrisorcin, acrivastine,acyclovir, adinazolam, adiphenine hydrochloride, adrafinil, adrenolone,agatroban, ahnitrine, akatinol, alatrofloxacin, albendazole, albuterol,aldioxa, alendronate, alfentanil, alibendol, alitretinoin, allopurinol,allylamines, allylestrenol, alminoprofen, almotriptan, alosetron,aloxiprin, alprazolam, alprenolol, amantadine, ambucetamide,amidephrine, amidinomycin, amiloride, aminoarylcarboxylic acidderivatives, aminoglutethimide, aminoglycosides, aminopentamide,aminopromazine, aminorex, amiodarone, amiphenazole, amiprilose,amisulpride, amitriptyline, amlexanox, amlodipine, amodiaquine,amosulalol, amotriphene, amoxapine, amoxicillin, amphecloral,amphetamine, amphomycin, amphotericin, ampicillin, ampiroxicam,amprenavir, amrinone, amsacrine, amyl nitrate, amylobarbitone,anagestone acetate, anastrozole, andinocillin, androstenediol,androstenediol-17-acetate, androstenediol-17-benzoate,androstenediol-3-acetate, androstenediol-3-acetate-17-benzoate,androstenedione, androsterone acetate, androsterone benzoate,androsterone propionate, androsterone, angiotensin, anidulatungin,aniracetam, apazone, apicycline, apoatropine, apomorphine,apraclonidine, aprepitant, aprotinin, arbaprostil, ardeparin,aripiprazole, amikacin, arotinolol, arstiinol, arylacetic acidderivatives, arylalkylamines, arylbutyric acid derivatives,arylcarboxylic acids, arylpiperazines, arylpropionic acid derivatives,aspirin, astemizole, atenolol, atomoxetine, atorvastatin, atovaquone,atropine, auranofn, azapropazone, azathioprine, azelastine,azetazolamide, azithromycin, baclofen, bambuterol, bamethan, barbitone,barnidipine, basalazide, beclamide, beclobrate, befimolol, bemegride,benazepril, bencyclane, bendazac, bendazol, bendroflumethiazide,benethamine penicillin, benexate hydrochloride, benfurodilhemisuccinate, benidipine, benorylate, bentazepam, benzhexyl,benziodarone, benznidazole, benzoctamine, benzodiazepine derivatives,benzodiazepine, benzonatate, benzphetamine, benzylmorphine, beperiden,bephenium hydroxynaphthoate, bepridil, betahistine, betamethasone,betaxolol, bevantolol, bevonium methyl sulfate, bexarotene,bezadoxifine, bezafibrate, bialamicol, biapenem, bicalutamide,bietamiverine, bifonazole, binedaline, binifibrate, biricodar,bisacodyl, bisantrene, bisoprolol, bitolterol, bopindolol, boswellicacid, bradykinin, bretylium, bromazepam, bromocriptine, bromperidol,brotizolam, brovincamine, buciclate, bucloxic acid, bucumolol,budralazine, buieniode, bufetolol, buflomedil, bufuralol, bumetanide,bunitrolol, bupranolol, buprenorphine, buproprion, buspirone, busulfan,butalamine, butarphenol, butaverine, butenafine, butenatme, butidrinehydrochloride, butobarbitone, butoconazole nitrate, butoconazole,butofilol, butorphenol, butropium bromide, cabergoline, calcifediol,calcipotriene, calcitriol, caldibine, cambendazole, camioxirole,camostat, camposterol, camptothecin, candesartan, candoxatril,capecitabine, caprate, capsaicin, captopril, carazolol, carbacephems,carbamates, carbamezepine, carbapenems, carbarsone, carbatrol,carbenoxolone, carbimazole, carbromal, carbuterol, carisoprodol,carotenes, caroverine, carteolol, carvedilol, cefaclor, cefazolin,cefbuperazone, cefepime, cefoselis, ceftibuten, celcoxib, celecoxib,celiprolol, cephaeline, cephalosporin C, cephalosporins, cephamycins,cerivastatin, certoparin, cetamolol, cetiedil, cetirizine, cetraxate,chloracizine, chlorambucil, chlorbetamide, chlordantoin,chlordiazepoxide, chlormadinone acetate, chlormethiazole, chloroquine,chlorothiazide, chlorpheniramine, chlorphenoxamide, chlorphentermine,chlorproguanil, chlorpromazine, chlorpropamide, chlorprothixene,chlortetracycline, chlorthalidone, cholecalciferol, chromonar,ciclesonide, ciclonicate, cidofivir, ciglitazone, cilansetron,cilostazol, cimetidine, cimetropium bromide, cinepazet maleate,cinnamedrine, cinnarizine, cinolazepam, cinoxacin, ciprofibrate,ciprofloxacin, cisapride, cisplatin, citalopram, citicoline,clarithromycin, clebopride, clemastine, clenbuterol, clidanac,clinofibrate, clioquinol, clobazam, clobenfurol, clobenzorex,clofazimine, clofibrate, clofibric acid, cloforex, clomipramine,clonazepam, clonidine, clonitrate, clopidogrel, clopirac indomethacin,cloranolol, cloricromen, clorprenaline, clortermine, clotiazepam,:clotrimazole, cloxacillin, clozapine, cmepazide, codeine methyl bromide,codeine phosphate, codeine sulfate, codeine, colloidal bismuthsubcitrate, cromafiban, cromolyn, cropropamide, crotethamide, curcumin,cyclandelate, cyclarbamate, cyclazocine, cyclexedrine, cyclizine,cyclobenzaprine, cyclodrine, cyclonium iodide, cyclopentamine,cyclosporin, cypionate, cyproheptadine, cyproterone acetate, cytarabine,dacarbazine, dalfopristine, dantrolene sodium, dapiprazole, darodipine,decanoate, decitabine, decoquinate, dehydroemetine, delavirdine, delaviridine, demeclo cycline, denopamine, deramciclone, descitalopram,desipramine, desloratadine, 3-ketodesogeskel, desomorphine,desoxymethasone, detomidine, dexamphetamine, dexanabinol,dexchlorpheniramine, dexfenfluramine, dexmethylphenidate, dexrazoxane,dextroamphetamine sulfate, dextroamphetamine, dextropropoxyphene, DHEA,diacetate, diamorphine, diazemine, diazepam, diaziquinone, diazoxide,dibromopropamidine, dichlorophen, diclofenac, dicoumarol, didanosine,dideoxyadenosine, diethylpropion, difemerine, difenamizole, diflunisal,digitoxin, digoxin, dihidroergotamine, dihydrocodeine, diLydrocodeinoneenol acetate, dihydroergotamine mesylate, dihydroergotamine,dihydrogesterone, dihydromorphine, dihydropyridine derivatives,dihydrostreptomycin, dihydrotachysterol, dihydroxyaluminumacetylsalicylate, diiodohydroxyquinoline, diisopromine, dilazep,dilevalol, dilitazem, diloxanide furoate, diloxanide, diltiazem,dimefline, dimenhydrinate, dimethisterone, dimetotrine, dimorpholamine,dinitolmide, dioxaphetyl butyrate, dioxethedrine, diphemethoxidine,diphenhydramine, diphenoxylate, diphetarsone, dipivefrin, diponiumbromide, dipyridamole, dirithromycin, disopyramide, divalproex sodium,dofetilide, domperidone, donezepil, dopexamine, dopradil, dosmalfate,doxapram, doxazosin, doxefazepam, doxepin, doxycycline, drofenine,dromostanolone propionate, dromostanolone, dronabinol, droperidol,droprenilamine, d-threo-methylphenidate, duloxetine, ebrotidine,eburnamonine, ecabet, ecenofloxacin, econazole nitrate, edavarone,edoxudine, efavirenz, effivarenz, efloxate, eledoisin, eletriptan,elgodipine, ellipticine, emepronium bromide, emetine, enalapril,enanthate, encainide, enlopitat, enoximone, enprostil, entacapone,epanolol, ephedrine, epinastine, epinephrine, epirubicin, epleronone,eposartan, ergocalciferol, ergoloid mesylates, ergotamine, ertapenum,erythromycin, erytlirityl tetranitrate, esaprazole, escitalopram,esmolol, esomeprazole, esonarimod, estazolam, estradiol benzoate,estramustine, eskiol succinate, estrone acetate, estrone sulfate,etafedrine, etafenone, ethacrynic acid, ethamivan, ethinamate,ethinyleskadiol 3-acetate, ethinyleskadiol 3-benzoate, ethinylestradiol,ethionamide, ethisterone (17a-ethinyltestosterone), ethopropazine,ethotoin, ethoxyphenamine, ethylestrenol, ethylmorphine,ethylnorepinephrine, ethynodiol diacetate, etodolac, etofibrate,etoposide, etoricoxib, etretinate, everolimus, exalamide, examestane,examorelin, ezemitibe, falecalcitriol, famciclovir, famotidine,fantofarone, farapenum, farglitazar, fasudil, felbamate, felodipine,fenalamide, fenbuLen, fenbutrazate, fendiline, fenfluramine, fenoldopam,fenoprofen, fenoterol, fenoverine, fenoxazoline, fenoxedil, fenpiprane,fenproporex, fenspiride, fentanyl, fexofenadine, flavoxate, flecainide,flopropione, floredil, floxuridine, fluconazole, flucytosine,fludarabine, fludiazopam, fludrocortisone, flulenamic acid, flunanisone,flunarizine, flunisolide, flunitrazepam, fluocortolone, fluoxetine,flupenthixol decanoate, fluphenazine decanoate, fluphenazine enanthate,fluphenazine, fluproquazone, flurazepam, flurbiprofen, fluorogestoneacetate, fluticasone propionate, fluvastatin, fluvoxamine, fominoben,formoterol, foscarnet, foscarnet, fosinopril, fosphenyloin,frovatirptan, fudosteine, fumagillin, furazolidone, furazolidone,furfurylmethyl amphetamine, furosemide, gabapentin, gabexate, gaboxadol,galanthamine, gallopamil, gammaparin, gancyclovir, ganglefene,gefarnate, gemcitabine, gemfibrozil, gepirone, gestadene, ghrelin,glatiramer, glaucarubin, glibenclamide, gliclazide, glimepiride,glipizide, gluconic acid, glutamicacid, glyburide, glyceryl trinitrate,glymepiride, granisetron, grepafloxacin, griseofulvin, guaiazulene,guanabenz, guanfacine, halofankine, haloperidol decanoate, haloperidol,haloxazolam, hepronicate, heptanoate, hexobendine, hexoprenaline,hydramitrazine, hydrazides, hydro chlorothi azide, hydrocodone,hydrocortisone, hydromorphone, hydroxyamphetamine,hydroxymethylprogesterone acetate, hydroxymethylprogesterone,hydroxyprogesterone acetate, hydroxyprogesterone caproate,hydroxyprogesterone, hymecromone, hyoscyamine, ibopamine, ibudilast,ibutenac, ibuprofen, ibutilide, idoxuridine, ifenprodil, igmesine,iloprost, imatinib, imidapril, imidazoles, imipenem, imipramine,imolamine, incadronic acid pergolide, indanazoline, indenolol,indinavir, indomethacin, indoramin, inosinepranobex, inositol niacinate,iodoquinol, ipidracine, iproniazid, irbesartan, irinotecan, irsogladine,isobutyrate, isocaprate esters, isoetharine, isometheptene,isoproterenol, isosorbide dinitrate, isosorbide mononitrate, isosorbidedinitrate, isoxsuprine, isradipine, itasetron, itraconazole,itramintosylate, ivermectin, kallidin, kallikrein, kanamycin, ketamine,ketoconazole, ketoprofen, ketorolac, ketotifen, labetalol, lafutidine,lamifiban, lamivudine, lamotrigine, lanatoside c, lansoprazole,lasofoxifene, leflunomide, leminoprazole, lercanadipine, lesopitron,letrozole, leucovorin, levalbuterol, levallorphan, levetiracetam,levetriacetam, levobunolol, levodopa, levofloxacin, levophacetoperane,levorphanol, lidocaine, lidoflazine, lifibrol, limaprost, linezolid,lintitript, liranaftate, lisinopril, lisuride, lobeline, lobucavir,lodoxamide, lomefloxacin, lomerizine, lomustine, loperamide, lopinavir,loprazolam, loracarbef, loratadine, lorazepam, lorefloxacin,lormetazepam, losartan, lovasatain, lovastatin, loxapine succinate,loxapine, 1-threo methylphenidate, lumiracoxib, lysine acetylsalicylate,lysozyme, lysuride, mabuterol, mafenide, magnesium acetylsalicylate,malgramostin, mannitol hexanitrate, maprotiline, mazindol, mebendazole,meclizine, meclofenamic acid, mecloxaminepentapiperide, medazepam,:medibazine, medigoxin, medrogestone, medroxyprogesterone acetate,mefenamic acid, mefenorex, mefloquin, mefloquine, megestrol acetate,melengestrol acetate, melphalan, mematine, mepenzolate bromide,meperidine, mephenoxalone, mephentermine, mepindolol, mepixanox,meprobamate, meptazinol, mercaptopurine, merropenum, mesalamine,mesalazine, mesoridazine besylate, mesoridazine, metaclazepam,metamfepramone, metampicillin, metaproterenol, metaraminol,methacycline, methadone hydrochloride, methadone, methamphetamine,methaqualone, methamphetamine, methoin, methotrexate, methoxamine,methsuximide, methylhexaneamine, methylphenidated-threo-methylphenidate, methylphenidate, methylphenobarbitone,methylprednisolone, methysergide, metiazinic acid, metizoline,metoclopramide, metolazone, metoprolol, metoxalone, metripranolol,metronidazole, mexiletine, mexilitene, metaxalone, mianserin,mibefradil, miconazole, midazolam, midodrine, miglitol, milnacipran,milrinone, minoxidil, mirtazapine, misoprostol, mitomycin, mitotane,mitoxantrone, mizolastine, modafinil, mofebutazone, mofetil, molindonehydrochloride, molindone, molsidomine, monatepil, montelukast,monteplase, moprolol, moricizine, morphine hydrochloride, morphinesulfate, morphine, morpholine salicylate, mosapramine, moxifloxacin,moxisylvyte, moxonidine, mycophenolate, nabumetone, nadolol, nadoxolol,nadroparin, nafamostat, nafronyl, naftopidil, nalbuphine, nalidixicacid, nalmefene, nalorphine, naloxone, naltrexone, nandrolone benzoate,nandrolone cyclohexanecarboxylate, nandrolone cyclohexane-propionate,nandrolone decanoate, nandrolone furylpropionate, nandrolonephenpropionate, naphazoline, naproxen, naratriptan, natamycin,nateglinide, nebivalol, nedocromil, nefazodone, nefopam, nelfinavir,nemonapride, neomycin undecylenate, neomycin, neokofin, nesiritide,n-ethylamphetamine, nevibulol, nevirapine, nexopamil, nicametate,nicardipine, nicergoline, nicofibrate, nicofuranose, nicomorphine,nicorandil, nicotinyl alcohol, nicoumalone, nifedipine, nifenalol,nikethamide, nilutamide, nilvadipine, nimodipine, nimorazole,nipradilol, nisoldipine, nitisonone, nitrazepam, nitrofurantoin,nitrofurazone, nitroglycerin, nizatidine, norastemizole, norepinephrine,norethynodrel, norfenefrine, norfloxacin, norgestimate, norgeskel,norgestrienone, normethadone, normethisterone, normorphine,norpseudoophedrine, nortriptyline, novantrone, nylidrin, nystatin,octamylamine, octodrine, octopamine, ofloxacin, olanzapine, olanzapine,olapatadine, olmesartan, olopatidine, olsalazine, omapatrilat,omeprazole, ondasetron, opium, oprevelkin, orlistat, ornidazole,ornoprostil, oseltamivir, oxaliplatin, oxamniquine, oxandrolone, oxantelembonate, oxaprozin, oxatomide pemirolast, oxatomide, oxazopam,oxcarbazepine, oxfendazole, oxiconazole, oxiracetam, oxolinicacid,oxprenol, oxycodone, oxyfedrine, oxymetazoline, oxymorphone,oxyphenbutazone, oxyphencyclimine, oxyprenolol, ozagrel, paclitaxel,palonosetron, pantoprazole, papaverine, paracalcitol, paramethadione,parecoxib, pariprazole, paromomycin, paroxetine, parsalmide,pazinaclone, pemoline, penbutolol, penciclovir, penicillin G benzathine,penicillin G procaine, penicillin V, penicillins, pentaerythritoltetranitrate,: pentaerythritol tetranitrate, pentapiperide, pentazocine,pentifylline, pentigetide, pentobarbitone, pentorex, pentoxifylline,pentrinitrol, perbuterol, perenzepine, pergolide, perhexyline,perindopril erbumine, perospone, perphenazine pimozide, perphenazine,phanquinone, phenacemide, phenacetin, phenazopyridine, phencarbamide,phendimetrazine, phenelzine, phenindione, phenmetrazine, phenobarbitone,phenoperidine, phenothiazines, phenoxybenzamine, phensuximide,phentermine, phentolamine, phenylsalicylate, phenylacetate,phenylbutazone, phenylephrinehydrochloride, phenylpropanolaminehydrochloride, phenylpropanolaminehydrochloride,phenylpropyl-methylamine, phenyloin, phloroglucinol, pholedrine,physostigwine salicylate, physostigmine, phytonadiol, phytosterols,piapenum, picilorex, piclamilast, picrotoxin, picumast, pifarnine,pilsicainide, pimagedine, pimeclone, pimecrolimus, pimethylline,pimozide, pinaverium bromide, pindolol, pioglitazone, piperacillin,piperazine estrone sulfate, piperazine derivatives, piperilate,piracetam, pirbuterol, pirenzepine, piribedil, pirifibrate, piroxicam,pitavastatin, pizotyline, plaunotol, polaprezinc, polybenzarsol,polyestrol phosphate, practolol, pralnacasan, pramipexole, pranlukast,pravastatin, prazepam, praziquantel, prazosin, pregabalin, prenalterol,prenylamine, pridinol, prifinium bromide, primidone, primipramine,probenecid, probucol, procainamide, procarbazine, procaterol,prochlorperazine, proguanil, pronethalol, propafenone, propamidine,propatyl nitrate, propentoffyline, propionate, propiram, propoxyphene,propranolol, propylhexedrine, propylthiouracil, protokylol,protriptyline, proxazole, pseudoephedrine, purines, pyrantel embonate,pyrazoles, pyrazolones, pyridofylline, pyrimethamine, pyrimidines,pyrrolidones, quazepam, quetiapine, quetuapine, quinagolide, quinapril,quinestrol, quinfamide, quinidine, quinine sulfate, quinolones,quinupritin, rabalzotan, rabeprazole sodium, rabeprazole, racefimine,ramahroban, ramipril, ranitidine, ranolazine, ransoprazole, rasagiline,rebamipide, refludan, repaglinide, repinotan, repirinast, reproterol,reserpine, retinoids, ribavirin, rifabutine, rifampicin, rifapentine,rilmenidine, riluzole, rimantadine, rimiterol, rioprostil, risperidone,ritanovir, ritapentine, ritipenem, ritodrine, ritonavir, rivastigmine,rizatriptan, rociverine, rofecoxib, rohypnol, rolipram, romoxipride,ronifibrate, ropinirole, ropivacaine, rosaprostol, rosiglitazone,rosuvastatin, rotinolol, rotraxate, roxatidine acetate, roxindole,rubitecan, salacetamide, salicin, salicylamide, salicylic acidderivatives, salmeterol, saquinavir, saquinavir, scopolamine,secnidazole, selegiline, semotiadil, sertindole, sertraline,sibutramine, sildenafil, simBibrate, simvastatin, siramesine, sirolimus,sitaxsentan, sofalcone, somotiadil, sorivudine, sotalol, soterenol,sparfloxacin, spasmolytol, spectinomycin, spiramycin, spizofurone,stavudine, streptomycin, succinylsulfathiazole, sucralfate, sufentanil,sulconazole nitrate, sulfacetamide, sulfadiazine, sulfaloxicacid,sulfarside, sulfmalol, sulindac, suloctidil, sulphabenzamide,sulphacetamide, sulphadiazine, sulphadoxine, sulphafurazole,sulphamerazine, sulphamethoxazole, sulphapyridine, sulphasalazine,sulphinpyrazone, sulpiride, sulthiame, sultopride, sulbroponium,sumanirole, sumahriptan, sunepihon, superoxide dismutase, suplatast,suramin sodium, synephrine, tacrine, tacrolimus, tacrolimus, tadalafil,talinolol, talipexole, tamoxifen, tamsulosin, targretin, tazanolast,tazarotene, tazobactum, tecastimezole, teclozan, tedisamil, tegaserod,telenzepine, telmisartan, temazepam, teniposide, teprenone, terazosin,terbenafine, terbinafine, terbutaline sulfate, terbutaline, terconazole,terfenadine, terodiline, terofenamate, tertatolol, testolactone,4-dihydrotestosterone, tetracyclics, tetracycline, tetrahydrocannabinol,tehrahydrozoline, thalidomide, theofibrate, thiabendazole,thiazinecarboxamides, thiocarbamates, thiocarbamizine, thiocarbarsone,thioridazine, thiothixene, tiagabine, tiamenidine, tianeptine,tiaprofenic acid, tiaramide, ticlopidine, tigloidine, tilisolol,timolol, tinidazole, tinofedrine, tinzaparin, tioconazole, tipranavir,tirapazamine, tirofiban, tiropramide, titanicene, tizanadine,tizanidine, tizinadine, tocainide, tolazamide, tolazoline, tolbutamide,tolcapone, tolciclate, tolfenamic acid, toliprolol, tolteridine,tolterodine, tonaberstat, topiramate, topotecan, torasemide, toremifenecibrate, toremifene, tosufloxacin, tramadol, tramazoline, trandolapril,tranilast, tranylcypromine, trapidil, traxanox, trazodone, tretoquinol,triacetin, triamcinolone, triampterine, triamterene, triazolam,trifluoperazine hydrochloride, trifluoperazine, triflupromazine,trihexyphenidyl, trimazosin, trimebutine, trimetazidine, trimethoprim,trimgestone, trimipramine, trimoprostil, trithiozine, troglitazone,trolnibrate phosphate, tromethamine, tropicamide, trovafloxacin,troxipide, tuaminoheptane, tulobuterol, tymazoline, tyramine,undecanoate, undecanoic acid, urinastatin, valacyclovir, valdecoxib,valerate, valganciclovir, valproic acid, valsartan, vancomycin,vardenafil, venlafaxine, venorelbine, verapamil, verapimil, vidarabine,vigabakin, vincamine, vinpocetine, viomycin, viquidil, visnadine,vitamin a derivatives, vitamin a, vitamin b₂, vitamin d, vitamin e,vitamin k, voglibose, voriconazole, xaliproden, xamoterol, xanthinolniacinate, xenytropium bromide, xibenolol, ximelagatran, xylometazoline,yohimbine, zacopride, zafirlukast, zalcitabine, zaleplon, zanamivir,zatebradine, ziconotide, zidovudine, zileuton, zimeldine, zincpropionate, ziprasidone, zolimidine, zolmitriptan, zolpidem, zonisamide,zopiclone, and mixtures thereof.

Formulation

The nebivolol compositions of the present invention may be administeredby various means, depending on their intended use, as is well known inthe art. For example, if compositions of the present invention are to beadministered orally, they may be formulated as tablets, capsules,granules, powders, suspensions or syrups. Alternatively, formulations ofthe present invention may be administered parenterally as injections(intravenous, intramuscular or subcutaneous), drop infusion preparationsor suppositories. For application by the ophthalmic mucous membraneroute, compositions of the present invention may be formulated aseyedrops or eye ointments. These formulations may be prepared byconventional means, and, if desired, the compositions may be mixed withany conventional additive, such as an excipient, a binder, adisintegrating agent, a lubricant, a corrigent, a solubilizing agent, asuspension aid, an emulsifying agent or a coating agent.

In formulations of the subject invention, wetting agents, emulsifiersand lubricants, such as sodium lauryl sulfate and magnesium stearate, aswell as coloring agents, release agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants may bepresent in the formulated agents.

Subject compositions may be suitable for oral, nasal, topical (includingbuccal and sublingual), rectal, vaginal, aerosol and/or parenteraladministration. The formulations may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. The amount of composition that may be combined with a carriermaterial to produce a single dose vary depending upon the subject beingtreated, and the particular mode of administration.

Methods of preparing these formulations include the step of bringinginto association compositions of the present invention with the carrierand, optionally, one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation agents with liquid carriers, or finely divided solidcarriers, or both, and then, if necessary, shaping the product.Formulations suitable for oral administration may be in the form ofcapsules, cachets, pills, tablets, lozenges (using a flavored basis,usually sucrose and acacia or tragacanth), powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia), each containing a predetermined amount of a subjectcomposition thereof as an active ingredient. Compositions of the presentinvention may also be administered as a bolus, electuary, or paste.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, lactose, sucrose, glucose,mannitol, and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, acetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.In the case of capsules, tablets and pills, the compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the subject compositionmoistened with an inert liquid diluent. Tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, may optionally bescored or prepared with coatings and shells, such as enteric coatingsand other coatings well known in the pharmaceutical-formulating art.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the subject composition, the liquid dosage formsmay contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn, germ, olive,castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the subject composition, may containsuspending agents such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating excipients or carriers comprising,for example, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the body cavity and release theactive agent. Formulations which are suitable for vaginal administrationalso include pessaries, tampons, creams, gels, pastes, foams or sprayformulations containing such carriers as are known in the art to beappropriate.

Dosage forms for transdermal administration of a subject compositionincludes powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. The active component may be mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to asubject composition, excipients, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays may additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Compositions of the present invention may alternatively be administeredby aerosol. This is accomplished by preparing an aqueous aerosol,liposomal preparation or solid particles containing the compound(s). Anon-aqueous (e.g., fluorocarbon propellant) suspension could be used.Sonic nebulizers may be used because they minimize exposing the agent toshear, which may result in degradation of the compounds contained in thesubject compositions.

Ordinarily, an aqueous aerosol is made by formulating an aqueoussolution or suspension of a subject composition together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularsubject composition, but typically include non-ionic surfactants(Tweens, Pluronics, or polyethylene glycol), innocuous proteins likeserum albumin, sorbitan esters, oleic acid, lecithin, amino acids suchas glycine, buffers, salts, sugars or sugar alcohols. Aerosols generallyare prepared from isotonic solutions.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise a subject composition in combination with one ormore pharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity may be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

Pharmaceutical formulations may also be extended or delayed releaseformulations where the active agents are released over an extendedperiod of time.

Dosages

Administration of the compositions of the present invention will be inan amount sufficient to achieve a therapeutic effect as recognized byone of ordinary skill in the art.

The dosage of any compositions of the present invention will varydepending on the symptoms, age and body weight of the patient, thenature and severity of the disorder to be treated or prevented, theroute of administration, and the form of the subject composition. Any ofthe subject formulations may be administered in a single dose or individed doses. Dosages for the compositions of the present invention maybe readily determined by techniques known to those of skill in the artor as taught herein.

In certain embodiments, the dosage of the subject compounds willgenerally be in the range of about 0.01 ng to about 10 g per kg bodyweight, specifically in the range of about 1 ng to about 0.1 g per kg,and more specifically in the range of about 100 ng to about 10 mg perkg.

An effective dose or amount, and any possible affects on the timing ofadministration of the formulation, may need to be identified for anyparticular composition of the present invention. This may beaccomplished by routine experiment as described herein, using one ormore groups of animals (preferably at least 5 animals per group), or inhuman trials if appropriate. The effectiveness of any subjectcomposition and method of treatment or prevention may be assessed byadministering the composition and assessing the effect of theadministration by measuring one or more applicable indices, andcomparing the post-treatment values of these indices to the values ofthe same indices prior to treatment.

The precise time of administration and amount of any particular subjectcomposition that will yield the most effective treatment in a givenpatient will depend upon the activity, pharmacokinetics, andbioavailability of a subject composition, physiological condition of thepatient (including age, sex, disease type and stage, general physicalcondition, responsiveness to a given dosage and type of medication),route of administration, and the like. The guidelines presented hereinmay be used to optimize the treatment, e.g., determining the optimumtime and/or amount of administration, which will require no more thanroutine experimentation consisting of monitoring the subject andadjusting the dosage and/or timing.

While the subject is being treated, the health of the patient may bemonitored by measuring one or more of the relevant indices atpredetermined times during the treatment period. Treatment, includingcomposition, amounts, times of administration and formulation, may beoptimized according to the results of such monitoring. The patient maybe periodically reevaluated to determine the extent of improvement bymeasuring the same parameters. Adjustments to the amount(s) of subjectcomposition administered and possibly to the time of administration maybe made based on these reevaluations.

Treatment may be initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage may be increased bysmall increments until the optimum therapeutic effect is attained.

The use of the subject compositions may reduce the required dosage forany individual agent contained in the compositions (e.g., the steroidalanti inflammatory drug) because the onset and duration of effect of thedifferent agents may be complimentary.

Toxicity and therapeutic efficacy of subject compositions may bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the LD₅₀ and the ED₅₀.

The data obtained from the cell culture assays and animal studies may beused in formulating a range of dosage for use in humans. The dosage ofany subject composition lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For compositions ofthe present invention, the therapeutically effective dose may beestimated initially from cell culture assays.

In general, the doses of an active agent will be chosen by a physicianbased on the age, physical condition, weight and other factors known inthe medical arts.

Efficacy of Treatment

The efficacy of treatment with the subject compositions may bedetermined in a number of fashions known to those of skill in the art.

In one exemplary method, the median rate of decrease in inflammation fortreatment with a subject composition may be compared to other forms oftreatment with the particular cardiovascular agent contained in thesubject composition, or with other cardiovascular agents. The decreasein inflammation for treatment with a subject composition as compared totreatment with another method may be 10, 25, 50, 75, 100, 150, 200, 300,400% greater or even more. The period of time for observing any suchdecrease may be about 1, 3, 5, 10, 15, 30, 60 or 90 or more hours. Thecomparison may be made against treatment with the particularcardiovascular agent contained in the subject composition, or with othercardiovascular agents, or administration of the same or different agentsby a different method, or administration as part of a different drugdelivery device than a subject composition. The comparison may be madeagainst the same or a different effective dosage of the various agents.

Alternatively, a comparison of the different treatment regimensdescribed above may be based on the effectiveness of the treatment,using standard indices known to those of skill in the art. One method oftreatment may be 10%, 20%, 30%, 50%, 75%, 100%, 150%, 200%, 300% moreeffective, than another method.

Alternatively, the different treatment regimens may be analyzed bycomparing the therapeutic index for each of them, with treatment with asubject composition as compared to another regimen having a therapeuticindex two, three, five or seven times that of, or even one, two, threeor more orders of magnitude greater than, treatment with another methodusing the same or different cardiovascular agents.

Kits

This invention also provides kits for conveniently and effectivelyimplementing the methods of this invention. Such kits comprise anysubject composition, and a means for facilitating compliance withmethods of this invention. Such kits provide a convenient and effectivemeans for assuring that the subject to be treated takes the appropriateactive in the correct dosage in the correct manner. The compliance meansof such kits includes any means which facilitates administering theactives according to a method of this invention. Such compliance meansinclude instructions, packaging, and dispensing means, and combinationsthereof. Kit components may be packaged for either manual or partiallyor wholly automated practice of the foregoing methods. In otherembodiments involving kits, this invention contemplates a kit includingcompositions of the present invention, and optionally instructions fortheir use.

EXEMPLIFICATION Example 1 Measurements of NO Release from HumanEndothelium

All measurements presented were recorded in vitro using a sensitiveporphyrinic probe, as previously described. Malinski T, Taha Z., Nature.1992; 358:676-678; Malinski T, Czuchajowski L., Methods in Nitric OxideResearch. 1996:319-339. NO release was measured directly from HUVEC.HUVEC cells from Black and White donors were grown in Ham's F12K mediumwith 2 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate andsupplemented with 0.1 mg/ml heparin and 0.03-0.05 mg/ml endothelial cellgrowth supplement (ECGS)+10% fetal bovine serum. The HUVEC cells werekept in an atmosphere of elevated CO2 concentration (5%). Nebivolol wasobtained from Mylan Laboratories (Morgantown, W. Va.).

All measurements of endothelial NO release were conducted in Hank'sbalance solution at 37° C. Cell wells were transferred to a Faraday cageand a porphyrinic sensor (diameter 0.5 mm) was positioned at a distanceof 5±2 μm from the surface of the endothelial cells using an invertedmicroscope (Leica Microsystems, Wetzlar, Germany) and acomputer-assisted micromanipulator. The sensor operated with athree-electrode system: nanosensor (working electrode), saturatedcalomel electrode (reference electrode) and platinum wire (counterelectrode, 0.5 mm diameter). The three electrodes were connected to apotentiostat/galvanostat PAR273. The baseline was stabilized after about20 seconds. The test compounds were injected with a nanoinjector ontothe surface of the cells following solubilization in buffer. Cells wereincubated with the test compounds for a 24-hour period. The compoundswere then washed out of the system before being immediately reintroducedin order to evaluate the consequences of chronic treatment on NO releasefrom the cells. For additive experiments, cells were incubated with ACEinhibitor for 24 hours, the inhibitor was washed out of the system,nebivolol was added and the NO release measured. The currentproportional to the NO concentration was measured with the sensor, whichoperated in amperometric mode at a constant potential of 0.63V. Datawere acquired with the use of an IBM computer with custom software andamperograms (current vs. time curves) were recorded with a Guniry FAS1Femtostat (Warminster, Pa.). Maximum release of NO was produced using acalcium agonist (1 μM). By increasing cytoplasmic levels of calcium, theion can bind to calmodulin. The Ca2+-calmodulin complex is a cofactorfor endothelial NO synthase, along with FAD, FMN, Heme and BH4.

Nanosensors were prepared from carbon fibers. The size of the tip ofcarbon fiber was reduced from 6 μm to less than μm by temperaturecontrolled burning. The sensors were sensitized to NO by deposition ofelectrically conductive polymeric porphyrin and covered with a thinlayer of Nafion. The porphyrinic microsensor has a response time of 0.1ms at a micromolar NO concentration and 10 ms at the detection limit of1 nM.

The nanosensor for NO was calibrated using saturated solution(concentration 1.82 mM verified with the coulometric method). Linearcalibration curves were constructed for each sensor from 5×10−9 to3×10⁻⁶M NO before and after measurements of cell activity. Theconcentration-dependent effects of nebivolol and certain ACE-inhibitorson NO releasing capacity were tested using a calcium ionophore (A23187)that stimulates NO release, independently of G-protein-coupledreceptors. The data were presented as the mean±SEM for each of thetriplicate measurements. The data (calculation and plotting) weretransferred to Microcal Origin Software (OriginLab Corp., Northampton,Mass.).

The HUVEC preparation is stable over the course of these experimentswith the cells remaining viable in culture for >24 hours. Undernon-stimulating conditions, basal levels of NO release are very low (<30nM). Measurement of NO release as a function of treatment was conductedin individual endothelial cells. Multiple measurements of NO release canbe conducted on single cells following a brief refractory period. Forrobust statistical analysis, separate cells were used for eachconcentration and type of drug used in these analyses.

In FIG. 1, the extent of NO release from Black and White donors wasmeasured after chronic treatment with the ACE inhibitor, ramiprilat,followed by treatment with nebivolol (1 μM). At concentrations of 1, 5,and 10 μM ramiprilat, there were modest but significant effects in theability of nebivolol to increase NO release from Black and White donorendothelial cells. The magnitude of the increase is greater inendothelial cells from Black donors.

In FIG. 3, the extent of NO release from Black and White donors wasmeasured with nebivolol (1 μM) following chronic treatment with theACE-inhibitor, enalapril. As observed with ramiprilat (above), enalaprilsignificantly enhanced the ability of nebivolol to increase NO releaseat concentrations of 5 and 10 μM and 1, 5 and 10 μM in Black and Whitedonor cells, respectively. The magnitude of the increase is greater inendothelial cells from Blacks than Whites (FIG. 4).

There were significant concentration dependent effects on the ability ofnebivolol to enhance NO release from Black and White donor endothelialcells that had been chronically treated with ACE inhibitors.Additionally, this property of the drug appears to work independently ofβ1-adrenoceptor blockade. By promoting a more normal vascular physiologythrough an NO-dependent pathway, nebivolol treatment may have betterefficacy and fewer side effects as compared to agents that only inhibitthe sympathetic nervous system. These data further support thehypothesis that nebivolol may have distinct pharmacologic benefitsthrough modulation of endothelial function and NO metabolism.

INCORPORATION BY REFERENCE

All of the patents and publications cited herein are hereby incorporatedby reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein.

1-36. (canceled)
 37. A composition comprising nebivolol or apharmaceutically acceptable salt thereof, and an angiotensin II receptorantagonist (ARB) selected from the group consisting of olmesartan,valsartan, losartan, and combinations thereof, and pharmaceuticallyacceptable salts thereof.
 38. The composition of claim 37, wherein theARB is selected from the group consisting of losartan, valsartan, andcombinations thereof, and pharmaceutically acceptable salts thereof. 39.The composition of claim 37, wherein the ARB is losartan or apharmaceutically acceptable salt thereof.
 40. A method of treating orpreventing hypertension in a patient in need thereof, comprisingadministering to said patient an effective amount of nebivolol or apharmaceutically acceptable salt thereof, and an angiotensin II receptorantagonist (ARB) selected from the group consisting of olmesartan,valsartan, losartan, and combinations thereof, and pharmaceuticallyacceptable salts thereof.
 41. The method of claim 40, wherein the ARB isselected from the group consisting of losartan, valsartan, andcombinations thereof, and pharmaceutically acceptable salts thereof. 42.The method of claim 40, wherein the ARB is losartan or apharmaceutically acceptable salt thereof.
 43. A method of treating orpreventing cardiovascular disease in a patient in need thereof,comprising administering to said patient an effective amount ofnebivolol or a pharmaceutically acceptable salt thereof, and anangiotensin II receptor antagonist (ARB) selected from the groupconsisting of olmesartan, valsartan, losartan, and combinations thereof,and pharmaceutically acceptable salts thereof.
 44. The method of claim43, wherein the ARB is selected from the group consisting of losartan,valsartan, and combinations thereof, and pharmaceutically acceptablesalts thereof.
 45. The method of claim 43, wherein the ARB is losartanor a pharmaceutically acceptable salt thereof.